5-hydroxy-4-(4-phenyl-1-piperazinyl-hydrobenz(c,d)indoles

ABSTRACT

5-HYDROXY-4-SATURATED HETEROCYCLIC AMINO-1,2,2A,3,4,5HEXAHYDROBENZ(C,D)INDOLES ARE PREPARED BY AMINATION OF 1-BENZOYL -4,5 - EPOXY - 1,2,2A,3,4,5-HEXAHYDROBENZ(C,D) INDOLE WITH AN APPROPRIATE SECONDARY AMINO FOLLOWED BY DEBENZOYLATION AND IN TURN ARE CONVERTED, IF DESIRED, TO THE CORRESPONDING TETRAHYDRO COMPOUNDS BY DEHYDROGENATION. THE COMPOUNDS ARE USEFUL AS CENTRAL NERVOUS SYSTEM DEPRESSANTS.

3,705,161 -HYDROXY-4-(4-PHENYL-I-PIPERAZINYL- HYDROBENZ[c,d]INDOLES RajK. Razdan, Belmont, and Fatima N. Johnson, Arlington, Mass., assignors.to Arthur D. Little, Inc., Cambridge, Mass.

No Drawing. Original application Apr. 23, 1968, Ser. No. 723,572, nowPatent No. 3,575,989, dated Apr. 20, 1971. Divided and this applicationJuly 27, 1970, Ser.

Int. Cl. C07d 51/70 US. Cl. 260268 TR 3 Claims ABSTRACT OF THEDISCLOSURE 5-hydroxy-4-saturated heterocyclic amino-l,2,2a,3,4,5-hexahydrobenz[c,d]indoles are prepared by amination of l-benzoyl 4,5epoxy 1,2,2a,3,4,5-hexahydrobenz[c,d] indole with an appropriatesecondary amino followed by debenzoylation and in turn are converted, ifdesired, to the corresponding tetrahydro compounds by dehydrogenation.The compounds are useful as central nervous system depressants.

This application is a divisional of our copending application Ser. No.723,572, filed Apr. 23,1968, now US. Pat. 3,575,989.

This invention relates to chemical compositions of matter classified as1,2,2a,3,4,5 hexahydrobenz[c,d]indoles and1,3,4,5-tetrahydrobenz[c,d]indoles.

The invention sought to be patented resides in the concept of 5hydroxy-4-(N=B)-1,2,2a,3,4,5 hexahydrobenz[c,d]indoles and 5hydroxy-4-(N=B)-l,3,4,5-tetrahydrobenz[c,d]indoles having the formulasHO N=B HO N=B wherein in each instance N=B is a saturated heterocyclicamino radical having 5 to 7 nuclear atoms, wherein Z is a saturatedbivalent radical selected from the group consisting of alkyleneoxadialkylene, thiadialkylene, azadialkylene and N-phenylazadialkylene.These compounds have pharmacodynamic activity, being useful for exampleas central nervous depressants.

As used herein f' N z means a saturated heterocyclic amino radicalhaving 5 to 7 nuclear atoms and thus includes pyrrolidyl,2,5-dimethylpyrrolidyl, 2 methylpyrrolidyl, 2 isopropylpyrrolidyl andlike alkylpyrrolidyl groups, piperidyl, S-ethylpiperidyl, 2,6dimethylpiperidyl and like alkylpiperidyl groups, 4-morpholinyl,2,6-diethyl-4-morpholinyl, 2-ethyl- 4-morpholinyl and likealkylmorpholinyl groups, 4-thiamorpholinyl, 2,6dimethyl-4thiamorpholinyl, 6-ethyl-4- thiamorpholinyl and likealkylthiamorpholinyl groups, piperazinyl, 4 lower-alkyl l piperazinyl, 4phenyll-piperazinyl, hexamethyleniminyl and the like; and Z is thereforea saturated bivalent radical selected from alkylene, oxadialkylene,thiadialkylene, and N-phenylazadinited States Patent 0 3,75,161 PatentedDec. 5, 1972 Too alkylene including for example tetramethylene,pentamethylene, hexamethylene, CH OCH CI-I N(CH2CH2)2C6H5, and the like.

The tetraand hexahydrobenz[c,d]indo1es of the invention are obtained byinteracting l-benzoyl-S-hydroxy- 4-(N=B)-1,2,2a,3,4,5hexahydrobenz[c,d]indole with aqueous alcoholic sodium hydroxide atreflux temperature in an inert atmosphere, as for example nitrogen. Thereaction mixture thus obtained is extracted with an organic solvent, asfor example, chloroform, ether, benzene or toluene and the organic layeris separated, filtered, concentrated and, if desired, purified to yield5-hydroxy-4- (N=B)-l,2,2a,3,4,5 hexahydrobenz[c,d]indole. The lattercan, if desired, be dehydrogenated over palladium in boiling xylene, toyield 5-hydroxy-4-(N=B)-1,3,4,5-tetrahydrobenz[c,d]indole.

The intermediate 1-benzoyl-5-hydroxy-4- (N=B 1,2,2a,3,4,5-hexahydrobenz[c,d]indoles are prepared by interacting the knownl-benzoyl-4,5-epoxy-l,2,2a,3,4,5-hexahydrobenz[c,d]indole with asecondary amine HN=B, wherein N=B has the same significance indicatedhereinabove, at about l00-l50 C. in an inert atmosphere as for examplenitrogen. The amine is used in excess of equimolar amounts andconveniently is employed as a solvent medium in which case the reactionis preferably carried out at the reflux temperature. The reactionmixture thus obtained is distilled under reduced pressure to removeexcess amine and the residue purified to yield the l-benzoyl-5-hydroxy-4-(N=B) 1,2,2a,3,4,5 hexahydrobenz[c,d] indole.

Due to the presence of a basic tertiary amino grouping, the compounds ofthis invention react with organic and inorganic acids to formacid-addition salts. These acidaddition salts are prepared from anyorganic acid, inorganic acid (including organic acids having aninorganic group therein), or organo-metallic acid as exemplified byorganic monoand poly-carboxylic acids such as found, for example, inBeilsteins Organische Chemie, 4th ed., Volumes III, IV, IX, X, XIV,XVII, XIX, XXI, XXII and XXV; organic mono and polysulfonicacid-sulfinic acids such as found, for example in Beilstein Volumes VI,XI, XVI, and XXII; organic phosphonic and phosphinic acids such asfound, for example, in Beilstein Volumes XI and XVI; organic acids ofarsenic and antimony such as found, for example, in Beilstein VolumeXVI; organic heterocyclic carboxylic, sulfonic, and sulfinic acids suchas found, for example, in Beilstein Volumes XVIII, XXII, and XXV; acidicion-exchange resins; and inorganic acids of any acid forming element orcombination of elements such as found in Mellor, Comprehensive Treatiseon Inorganic and Theoretical Chemistry, Longmans, Green and Co., NewYork, NY. Volumes I-XVI. In addition, other saltforming compounds whichare acidic in their chemical properties but which are not generallyconsidered as acids in the same sense as carboxylic or sulfonic acidsare also considered tobe among the numerous acids which can be used toprepare the acid-addition salt forms of the compounds of this invention.Thus there are also included acidic phenolic compounds such as found,for example, in Volume VI of Beilstein, acidic compounds havingactivated or acidic hydrogen atoms, as for example, picrolonic acid, orbarbituric acid derivatives having an acidic proton such as found, forexample, in Cox et a1. Medicinal Chemistry, vol. IV, John Wiley & Sons,Inc., New York, NY. (1959).

Representative acids for the formation of the acid-addition saltsinclude formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaricacid, succinic acid, succinamic acid, glutamic acid, tartaric acid,oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid,gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid,phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilicacid, cholic acid, Z-pyridine-carboxylic acid, pamoic acid,3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid,3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonicacid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid,acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid,hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoricacid, hydrocyanic acid, phosphotungstic acid, molybdic acid, arsenicacid, and the like. The acid-addition salts with lactic acid and withethanesulfonic acid, for example, are water-soluble.

The acid-addition salts are prepared in conventional fashion, forinstance either by direct mixing of the acid and the free base form or,when this is not appropriate, by dissolving either or both of the acidand the free base form separately in Water or an organic solvent andmixing the two solutions, or by dissolving both the acid and the freebase form together in a solvent. The resulting acid-addition salt isisolated by filtration, if it is insoluble in the reaction medium, or byevaporation of the reaction medium to leave the acid-addition salt as aresidue. The acid moieties or anions in these salt forms are inthemselves neither novel nor critical and therefore can be any acidanion or acid-like substance capable of salt formation with the freebase form of our compounds.

The acid-addition salt forms of the new compounds are useful not only ascentral depressants as herein indicated, but are also useful forcharacterizing and identifying purposes, and in isolation orpurification procedures. Moreover, the acid-addition salts are sourcesof the free base forms, for instance by reaction with strong bases, andaccordingly all of the acid-addition salts, regardless of considerationsof solubility, toxicity, physical form, or the like of a particularsalt, are useful for the purposes of our invention.

It will be appreciated from the above that if one or more of thecharacteristics, such as solubility, molecular weight, physicalappearance, toxicity, or the like of a given free base or acid-additionsalt form of a particular compound render that form less suitable forthe purpose at hand, it can be readily converted to another, moresuitable form.

The structure of the compounds of this invention followed from themethods of synthesis which were used and from the elementary analyses ofthe products obtained.

The invention is illustrated by the following examples without, however,being limited thereto.

EXAMPLE 1 (a) '1-benzoyl-5-hydroxy-4-piperidyl-1,2,2a,3,4,5-

hexahydrobenz [c,d] indole A solution of 2 g. ofl-benzoyl-4,5-epoxy-l,2,2a,3,4,5- hexahydrobenz[c,d]indole in 40 ml. ofpiperidine was stirred and refluxed for eighteen hours under nitrogen.The excess amine was removed by distillation under reduced pressure andthe residue recrystallized from a benzene/petroleum ether mixture. Aftertwo recrystallizations from benzene there was obztained 2 g. ofl-benzoyl- 5-hydroxy-4-piperidyl 1,2,2a,3,4,5 hexahydrobenz[c,d] indole,M.P. 190-192 C.

(b) 5-hydroxy-4-piperidyl-l,2,2a,3,4,5-hexahydrobenz[c,d] indole Amixture of 1.9 g. of 1-benzoyl-5-hydroxy-4-piperidyl-1,2,2a,3,4,5-hexahydrobenz[c,d]indole and 2.2 g. of sodium hydroxide in45 ml. of 66% aqueous ethanol was refluxed under nitrogen for twenty-onehours. The cooled solution was extracted with benzene, the benzeneextracts washed with water and dried. Evaporation of the solvent underreduced pressure gave a solid which was collected by filtration thenrecrystallized from carbon tetrachloride to give 0.95 g. of5-hydroxy-4-piperidyl-1,2,2a,3,4,5-hexahydrobenz[c,d]indole, M.P. l45l47C. dec.

(0) 5-hydroxy-4-piperidyl-l,3,4,5-tetra hydrobenz [c,d] indole Asolution of 400- mg. of 5-hydroxy-4-piperidyl-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 18 ml. of dry xylene containing 400mg. of 10% palladium-on-charcoal was refluxed for thirty minutes thenfiltered through a sintered glass funnel to remove the catalyst. Thefiltrate was concentrated to about 1 ml. then taken up in 25 ml. ofether and saturated with dry hydrogen chloride. After removal of theether under a stream of nitrogen the resultant solid was dissolved in aminimum amount of methanol and the solution diluted with ether. Thesolid which separated was collected by filtration to give 165 mg. of5-hydroxy-4-piperidyl 1,3,4,5 tetrahydrobenz [c,d]indole hydrochloride,M.P. 230 C. dec. The free base was liberated by dissolving thehydrochloride in a minimum amount of water and adding an excess of 5%sodium hydroxide. The solid which precipitated was collected, dried andrecrystallized from a 2:1 hexane/benzene mixture to give mg. of5-hydroxy-4-piperidyl- 1,3,4,5-tetrahydrobenz[c,d]indole, M.P. 144-145C.

EXAMPLE 2 (a) 1 benzoyl-5-hydroxy-4-(4-phenyl-l-piperazinyl)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole was prepared from 2 g. of1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz [c,d] indole and 10 m1.of phenylpiperazine using the procedure described in Example 1a. Afterrecrystallization from methanol there was obtained 2 g. of l-benzoyl-S-hydroxy-4-(4-phenyl-l-piperazinyl)-l,2,2a,3,4,5hexahydrobenz[c,d]indole, M.P. 204-206 C.

(b) 5-Hydroxy-4-(4-phenyl-l-piperazinyl)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole was prepared from 2 g. of 1- benzoyl5-hydroxy-4-(4-phenyll-piperazinyl -1,2,2a,3 ,4,5-hexahydrobenz[c,d]indole, 1.8 g. of sodium hydroxide, 30 ml. ofethanol and 15 ml. of water using the procedure described in Example lb.There was thus obtained 1.3 g. of 5 hydroxy4-(4-phenyl-1-piperazinyl)-1,2,2a,3,4,5- hexahydrobenz[c,d]indole, M.P.162-163 C.

(c)'5-hydroxy-4a(4-phenyl-1-piperazinyl)-1,3,4,5-tetrahydrobenz[c,d]indole.-Asolution of 100 mg. of 5-hydroxy4-(4-phenyl-l-piperazinyl)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole in 15ml. of chloroform was saturated with hydrogen chloride and the solidhydrochloride which precipitated washed by decantation with ether. Thedry solid was dissolved in 10 ml. of water and added to a suspension ofone-half a teaspoon of activated Raney nickel in 20 ml. of water and themixture refluxed for four hours. The aqueous portion was decanted fromthe white solid which separated and extracted with chloroform. Thechloroform extracts were dried and the solvent removed by distillationunder reduced pressure. The residual oil crystallized upon triturationwith methanol and was collected by filtration. Recrystallization frommethanol gave 15 mg. of 5 hydroxy-4-(l-phenyl-l-piperazinyl)-1,3,4,5-tetrahydrobenz[c,d]indole, M.P. 200 C.

The following are further illustrative examples of the 5- hydroxy 4(N=B) 1,2,2a,3,4,5-hexahydrobenz[c,d] indole and 5 hydroxy-4-(NB)-1,3,4,5-tetrahydrobenz [c,d]indole which are obtained by proceedingin accordance with the methods hereinabove described:

5-hydroxy-4-pyrrolidyl-1,2,2a,3,4,5-hexahydrobenz[c,d]

indole;

5-hydroxy-4-pyrrolidinyl-1,3,4,5-tetrahydrobenz[c,d]

indole;

5-hydroxy-4-(2,6-dimethyl-l-piperidyl)-1,2,2a,3,4,5-

hexahydrobenz[c,d] indole;

5-hydroXy-4-(2,6-dimethyl-l-piperidyl) -1,3,4,5-tetrahydrobenz [c,d]indole;

S-hydroxy-4-hexamethyleniminyl-1,2,2a,3 ,4,5-hexahydrobenz [c,d] indole;

5-hydroxy-4-(4-morpholinyl) -1,3,4,5-tetrahydrobenz [c,d] indole;

5-hydroxy-4-(1-piperazinyl)-1,2,2a,3 ,4,5-hexahydrobenz [c,d] indole;

S-hydroxy-Z- (4-thiamorpholinyl 1,3 ,4,5-tetrahydrobenz [c,d] indole;

5-hydroxy-4-hexamethyleniminyl-1,3,4,5-tetrahydrobenz [c,d] indole;

5-hydroxy-4-( l-homopiperazinyl) 1,2,2a,3,4,5-hexahydrobenz [c,d]indole; and

S-hydroxy-4- (6-methyl-1-piperidinyl)-1,3 ,4,5-tetrahydrobenz [c,d]indole.

The 5 hydroXy-4-(N==B)-1,2,2a,3,4,5-hexahydrobenz [c,d]indoles and 5hydroxy-4-(N=)-1,3,4,5-tetrahydro [c,dJindoles at intravenous dosages or15 to 30 mg./kg. induce in mice a general activity decrease as comparedto control animals when tested according to the procedure described byIrwin, Animal and Clinical Pharmacologic Techniques in Drug Evaluation(edited by Nodine and Siegler), Year Book Medical Publishers, Inc.,Chicago, Ill. 1964, p. 46.

The compounds of the invention are prepared for use by conventionalpharmaceutical formulation procedures; that is, in capsule or tabletform with conventional excipients (for example, calcium carbonate,starch, lactose, talc, magnesium stearate, gum acacia, and the like) fororal administration; or as an aqueous or oil solution or suspension in apharmaceutically acceptable vehicle (water, aqueous alcohol, oilsolution or oil-water emulsion) for oral or parenteral administration.

We claim:

1. A compound of the group consisting of 5-hydroxy-4- (N B) 1,2,2a,3,4,5hexahydrobenz[c,d]indole and 5- hydroxy 4 (NB)-1,3,4,5-tetrahydrobenz[c,d]indole wherein N B is l-piperazine(4-phenyl).

2. 5 hydroXy-4-(4-phenyl-1-piperazinyl)-1,2,2a,3,4,5-hexahydrobenz[c,d]indole according to claim 1 wherein Z isN-phenylazadiethylene.

3. 5hydroxy-4-(4-phenyl-l-piperazinyl)-1,3,4,5-tetrahydrobenz[c,d]indoleaccording to claim 1 wherein Z is N-phenylazadiethylene.

References Cited Stoll et al., Chem. Abstr. vol. 46, col. 123g (1952).

DONALD G. DAUS, Primary Examiner

